HIV-1 infection is today perceived as an incurable chronic viral infection in which lifelong combination antiretroviral therapy (cART) is needed to avoid disease (Egger, Hirschel et al. 1997, Palella, Delaney et al. 1998). Very early during acute HIV infection a latent reservoir is established and despite effective cART, HIV-1 persists in latently infected cells (Dai, Agosto et al. 2009, Carter, Onafuwa-Nuga et al. 2010, Wightman, Solomon et al. 2010). Upon treatment interruption, the virus quickly replicates, and viremia rebounds to pre-treatment levels. In the inactive, resting state latently infected cells are unrecognizable to the immune system and unresponsive to antiretroviral drugs (Chun, Stuyver et al. 1997, Finzi, Hermankova et al. 1997). The size of the reservoir likely varies between individuals and may be influenced by a number of different factors such as host immune constitution, time from diagnosis to initiation, level of persistent immune activation, antiretroviral treatment regimens used and individual response to treatment. Earlier studies employing viral outgrowth assays indicated that the number of latent CD4 T cells harboring replication-competent virus was approximately 1 per 106 cells.
A broad range of bioanalytical assays have been used in the attempt to quantify the reservoir but it is currently unclear which assay(s) should be used to monitor HIV-1 reservoirs in clinical studies of eradication strategies (Eriksson, Graf et al. 2013). Upon activation, resting T cells carrying replication competent integrated proviral DNA are capable of resuming HIV transcription (Chun, Finzi et al. 1995, Chun, Carruth et al. 1997, Eriksson, Graf et al. 2013). One of the proposed ways of curing HIV-1 is to activate and kill latently infected cells in the presence of antiretroviral therapy (Deeks 2012). Epigenetic modulation of the molecular mechanisms that block transcription of integrated HIV DNA can reactivate HIV-1 expression in resting infected memory CD4 T cells and disrupt latency (Rasmussen, Schmeltz Sogaard et al. 2013, Rasmussen, Tolstrup et al. 2013). Histone deacetylase inhibitors (HDACi) turn on genes by promoting acetylation of lysine residues on histones (Van Lint, Emiliani et al. 1996, Tyagi, Pearson et al. 2010). This induces chromatin relaxation and transcriptional activation. The HDACi romidepsin (Celgene) potently activates HIV-1 expression in latently infected cell lines and primary T cells (Geleziunas 2013).
Vacc-4x is a peptide-based HIV-1 therapeutic vaccine that aims to improve immune responses to p24Gag since this has been associated with slower disease progression and improved virus control (Kiepiela 2007; Zuniga 2006). The primary objective of Vacc-4x immunization is to strengthen the immune system's response to HIV p24. The enhanced immune response to HIV-1 following immunization with Vacc-4x could improve the host immune system as part of an HIV functional cure treatment strategy.
In one of the largest randomized, placebo controlled HIV therapeutic vaccine trials conducted to date (study CT-BI/Vacc-4x/2007/1), Vacc-4x and rhuGM-CSF (Leukine®) as adjuvant showed a significant reduction in viral load (VL) set point in the Vacc-4x group as compared to placebo and a significant reduction in VL set point from historic preART values, despite higher preART values being present in the Vacc-4x group as compared to placebo. Additionally Vacc-4x was shown to be immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell.
New HIV p24 peptides are described in WO91/13360, wherein the peptides are used in a method of discriminating between a false and true diagnosed HIV-positive serum sample.
Johnson R. P., et al., The Journal of Immunology, Vol. 147, p. 1512-1521, No. 5, Sep. 1, 1991 describe an analysis of the fine specificity of gag-specific CTL-responses in three HIV-1 seropositive individuals, the gag-specific CTL-responses were found to be mediated by CD3+CD8+ lymphocytes which are HLA class I restricted.
EP-A-0 356 007 discloses antigenic determinants, in particular it relates to synthetic polypeptide sequences which are related to proteins present in the HIV-1 and which can be used as a basis for a potential vaccine against AIDS.
Rosenberg E. S. et al., Science, Vol. 278, 21 Nov. 1997, p. 1447-1450 describe that virus specific CD4+ T helper lymphocytes are critical to the maintenance of effective immunity in a number of chronic viral infections, but are characteristically undetectable in chronic human immunodeficiency virus-type 1 (HIV-1) infection. HIV-1-specific proliferative responses to p24 were inversely related to viral load. They conclude that the HIV-1-specific helper cells are likely to be important in immunotherapeutic interventions and vaccine development.
EP 0 230 222, EP 0 270 114, DE 37 11 016 and GB 2 188 639 all in the name of F. Hoffmann-La Roche & Co. Aktiengesellschaft concern recombinant expression and purification of an HTLVIII Gag/Env gene protein or fusionproteins. The proteins consisting of native sequences can be purified to homogeneity and used as a basis for diagnostic tests for detection of antibodies against viruses associated with AIDS. The gag/env protein may also be formulated for use as a vaccine for protection against AIDS through prophylactic immunization.
International Patent Application WO00/52040 discloses methods for treating HIV infections by administering e.g. HIV specific peptides based on conserved regions of HIV gag p24.
There is a need to provide improved methods for the treatment of HIV infections and AIDS.